"Small fiber neuropathy has been found in multiple chronic pain conditions so the meaning of this finding is unclear. Also, many cardinal symptoms of fibromyalgia (fatigue, sleep, memory, and mood disturbances) cannot be explained by neuropathy, and the distribution of the pain in fibromyalgia (e.g., headaches, irritable bowel, interstitial cystitis) doesn't match that of small fiber neuropathy. So we need to be careful about drawing conclusions from these findings," Clauw told MedPage Today.

The underlying pathophysiology associated with fibromyalgia continues to be uncertain, at least in part because of the lack of a specific tissue lesion.

"As a result, the idea has developed that a central nervous system origin for fibromyalgia is the only viable explanation for its existence," Caro and Winter wrote.

They noted that their interest into a potential peripheral nervous system origin for fibromyalgia stemmed from their observation that many patients described their pain in terms similar to those used by patients with peripheral neuropathy.

They previously explored this by electrodiagnostic testing and sural nerve biopsies, but such biopsies are difficult and expensive. More recently, reports have suggested that skin biopsies to quantitate epidermal nerve fiber density could be a useful tool for the evaluation of peripheral neuropathy.

The Clinical Study

Between January 2007 and August 2011 Caro and Winter assessed 41 consecutive patients who met the 1990 American College of Rheumatology criteria for fibromyalgia, along with 47 controls.

The majority were women. Mean ages were 61 years for patients and 48 for controls.

All patients showed a "stocking distribution" of diminished sensory perception.

Among other findings were:

A significant inverse correlation between age and calf epidermal nerve fiber density in patients (r=-0.29, P=0.03), though not controls

A trend toward a significant inverse correlation between epidermal nerve fiber density at the thigh and IL-2R in the fibromyalgia patients (r=-0.22, P=0.08)

A trend was toward significance between symptom duration and IL-2R (r=-0.24, P=0.07), though not with epidermal nerve fiber density at either calf or thigh

"As a signal, IL-2R has been thought reliable enough so that it has been used to monitor the course of some autoimmune diseases," Caro and Winter wrote.

In addition, patients' pain rating on a 10-point scale and physician global 3-point tenderness score correlated with each other (r=0.51, P=0.0005) although pain didn't correlate with nerve fiber density.

Pain and Immunity

Small fiber neuropathy is associated with both loss of sensation to the skin and peripheral pain, so the finding of the stocking distribution of diminished perception was "not unexpected," according to the authors.

"The painful peripheral symptoms of small fiber neuropathy, on the other hand, are thought to be due to a disproportionate hyperexcitability of the primary, lesioned -- but not altogether defunct -- small nerve fibers and a surrounding, structurally normal, but physiologically hyperexcitable group of secondary small nerve fibers responding collaterally," they wrote.

But small fiber neuropathy isn't an entirely new concept, according to Ali Askari, MD, of UH Case Medical Center in Cleveland.

"It has come to light in the last decade, and explains a lot of the uncomfortable feelings in the legs and hands and other parts of the body in fibromyalgia," Askari said in an interview.

"Nevertheless, in the absence of data implicating any other known neuropathic disorder in the genesis of this lesion, we consider it likely that an immunopathogenic mechanism is at work in this patient population," they wrote.

"According to our data, this nexus between the immune system and fibromyalgia is likely to be influenced by a T-cell mediated arm. It may also involve factors within a system commonly referred to as neurogenic inflammation," they added.

Another View

An editorial accompanying the study described the understanding of fibromyalgia as still incomplete.

"What we call fibromyalgia may be at the crossroads of different pathophysiological situations with a common clinical background phenotype," wrote Piercarlo Sarzi-Puttini, MD, and Fabiola Atzeni, MD, PhD, of Sacco University Hospital in Milan.

"Where does fibromyalgia originate? Is it due to a genetic and/or familial predisposition, a stress-related personality disorder, a psychoaffective disorder, or a post-traumatic stress disorder? It may be all of these or none," Sarzi-Puttini and Atzeni commented.

"All we can do is continue to look for tissue abnormalities and central processing alterations in an attempt to discover which come first, and then develop the best therapeutic (or, even better, preventive) strategy for the 2% to 3% of the population who suffer from the disease," the editorialists concluded.

Caro and Winter disclosed no relevant financial relationships.

Reviewed by Zalman S. Agus, MD Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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